{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T09:20:18Z","timestamp":1774084818303,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T00:00:00Z","timestamp":1708300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 Research and Innovation Programme","award":["734548"],"award-info":[{"award-number":["734548"]}]},{"name":"Fondation pour la Recherche Medicale (FRM)","award":["734548"],"award-info":[{"award-number":["734548"]}]},{"name":"Tuscany Region \u201cBando Regionale Ricerca Salute 2018\u2014TUSCAVIR.NET","award":["734548"],"award-info":[{"award-number":["734548"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Zika virus (ZIKV) is a positive-sense single-stranded virus member of the Flaviviridae family. Among other arboviruses, ZIKV can cause neurological disorders such as Guillain Barr\u00e9 syndrome, and it can have congenital neurological manifestations and affect fertility. ZIKV nonstructural protein 5 (NS5) is essential for viral replication and limiting host immune detection. Herein, we performed virtual screening to identify novel small-molecule inhibitors of the ZIKV NS5 methyltransferase (MTase) domain. Compounds were tested against the MTases of both ZIKV and DENV, demonstrating good inhibitory activities against ZIKV MTase. Extensive molecular dynamic studies conducted on the series led us to identify other derivatives with improved activity against the MTase and limiting ZIKV infection with an increased selectivity index. Preliminary pharmacokinetic parameters have been determined, revealing excellent stability over time. Preliminary in vivo toxicity studies demonstrated that the hit compound 17 is well tolerated after acute administration. Our results provide the basis for further optimization studies on novel non-nucleoside MTase inhibitors.<\/jats:p>","DOI":"10.3390\/ijms25042437","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T10:40:15Z","timestamp":1708339215000},"page":"2437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Novel Non-Nucleoside Inhibitors of Zika Virus NS5 Protein Targeting MTase Activity"],"prefix":"10.3390","volume":"25","author":[{"given":"Diego","family":"Fiorucci","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micaela","family":"Meaccini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulio","family":"Poli","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Alfreda","family":"Stincarelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 48, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4208-7760","authenticated-orcid":false,"given":"Chiara","family":"Vagaggini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-7621","authenticated-orcid":false,"given":"Simone","family":"Giannecchini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 48, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8672-690X","authenticated-orcid":false,"given":"Priscila","family":"Sutto-Ortiz","sequence":"additional","affiliation":[{"name":"AFMB, Aix-Marseille University, CNRS, UMR 7257, Case 925, 163 Avenue de Luminy, Cedex 09, 13288 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Canard","sequence":"additional","affiliation":[{"name":"AFMB, Aix-Marseille University, CNRS, UMR 7257, Case 925, 163 Avenue de Luminy, Cedex 09, 13288 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6046-024X","authenticated-orcid":false,"given":"Etienne","family":"Decroly","sequence":"additional","affiliation":[{"name":"AFMB, Aix-Marseille University, CNRS, UMR 7257, Case 925, 163 Avenue de Luminy, Cedex 09, 13288 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-940X","authenticated-orcid":false,"given":"Elena","family":"Dreassi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalaura","family":"Brai","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Botta","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1098\/rstb.2011.0354","article-title":"Human Viruses: Discovery and Emergence","volume":"367","author":"Woolhouse","year":"2012","journal-title":"Philos. 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